Systemic Sclerosis and Jak Inhibitors : Emphasis on Macrophages

Overview

The Sclero-JAK project aims to assess the impact of a JAK1/2 inhibitor (ruxolitinib) on activation states of monocytes-derived macrophages (MDM) from systemic sclerosis (SSc) patients

Systemic sclerosis is a fibrotic and inflammatory chronic autoimmune disorder with no disease modifiying drug available to date. JAK inhibitors may represent a relevant therapeutic candidate for this disease; The primary objective of this study is to characterize the impact of Ruxolitinib (a JAK ½ inhibitor) on the prof-fibrotic properties of MDM from SSc patients in vitro. The primary outcome will be the concentration of CCL18 evaluate by ELISA in the condition media of MDM from SSc patients pre treated or not in vitro by ruxolitinib. The secondary objectives : 1. To characterize the impact of ruxolitinib on other pro-inflammatory or pro-fibrotic cytokines 2. To characterize the impact of ruxolitinib on membrane expression of macrophagic polarization markers of MDM from SSc patients 3. To evaluate the impact of ruxolitinib on the phenotype of MDM from healthy donors exposed in vitro to the serum of SSc patients. 4. To determine the variability of the effects of ruxolitinib on MDM of SSc patients depending on key clinical characteristics (diffuse versus limited SSc, patients with or without Interstitial Lung disease ILD) The secondary outcomes : 1. ELISA of the following cytokine evaluated in the condition media of SSc MDM pre-treated or not with ruxolitinib : PDGFbb, IL-6, CXCL10, CXCL4 2. Membrane expression (flow cytometry) of the following markers expressed by SSc MDM pre-treated or not with ruxoltinib : CD204, CD206, CD163, CD86, CMHII, TLR4. 3. Evaluation of the same cytokines and membrane markers in MDM from HD exposed to serum media of SSc patients. 4. Variation of the effect of ruxolitinib on the primary outcome (CCL18 secreted in the condition media of MDM from SSc patients) in sub groups depending on the following characteristics : * Auto antibodies (anticentromere, antitopoisomerase, anti RNA polymerase III or none) * modified Rodnan skin score * Digital ulcers (current or past) * Pulmonary involvement (Interstitial Lung disease on CT scan) * Heart involvement (Pulmonary arterial hypertension on echocardiography)

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